BAD and BAX:14-3-3; BAD and BAX are proapoptotic proteins that are regulated by 14-3-3 proteins in the pancreatic b-cell. Modulation of BAD and BAX activity via stabilisation of their interactions with 14-3-3 could lead to improved treatments for diabetes.

AstraZeneca and TUE (Eindhoven University of Technology) will offer the PhD student a unique opportunity to gain world class knowledge and hands-on experience in various applications of medicinal chemistry and drug discovery at the forefront of biomedical research and development. The successful candidate will also participate in the network’s training activities and work placements at the laboratories of other participating academic and industrial teams. The degree will be awarded by Eindhoven University of Technology.

Projects:

Modulation of Protein-Protein Interactions (PPIs) with small molecules is one of the most promising and challenging areas in chemical biology and drug discovery. Whereas inhibition of PPIs is a well-documented and successful strategy, the opposite approach of small-molecule stabilization of PPIs has not been as extensively explored.

The adapter protein 14-3-3 acts as a “hub” by interacting with several hundred partner proteins in human cells. These 14-3-3 PPIs are implicated in a number of diseases ranging from cancer and neurodegeneration to inflammation and metabolic syndromes. In the Innovative Training Network TASPPI (Targeted Stabilization of Protein-Protein Interactions, www.tasppi.eu) we aim in a consortium of 5 universities (Dundee, Eindhoven, Leeds, Lille, Prague, Siena), 3 pharma companies (AstraZeneca, GSK, UCB), and 2 small-medium enterprises (LDC, Taros) to identify and optimize small-molecule 14-3-3 PPI stabilizers as novel tools for basic research and starting points for drug development.

The doctoral training positions advertised herein are to be filled at AstraZeneca R&D Gothenburg, Sweden in conjunction with Eindhoven University of Technology, The Netherlands (where the successful candidates will be registered for a PhD).

The position is available on the following research project:

BAD and BAX:14-3-3; BAD and BAX are proapoptotic proteins that are regulated by 14-3-3 proteins in the pancreatic b-cell. Modulation of BAD and BAX activity via stabilisation of their interactions with 14-3-3 could lead to improved treatments for diabetes.

Tasks include

The successful candidates will work together with 11 other PhD students within the TASPPI consortium and will be included in a network-wide training and secondment programme.

Assay development and screening for the identification of small-molecule stabilizers of the 14-3-3 interactions.

In silico modelling of 14-3-3 protein-protein interactions and the use of the derived models for virtual screening and structure-based design

A diploma and/or a master’s degree in chemistry, medicinal chemistry or chemical biology, preferably with a research project in organic synthesis

An excellent track record from previous studies along, with experience in at least one of these fields: organic synthesis, virtual screening, computational chemistry or medicinal chemistry. Good knowledge of peptide chemistry and biochemistry is a plus.

Fluent in the English language (spoken and written/proficiency level).